Metabolic syndrome has become a global epidemic that dramatically increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic steatohepatitis. Skeletal muscle insulin resistance is a hallmark of the metabolic derangements in this syndrome that has been associated with impaired mitochondrial oxidative capacity and a shift from oxidative to glycolytic myofiber types. However, the cause and effect relationship between the metabolic properties of skeletal myofibers and insulin sensitivity remains unclear. While the PGC-1 coactivators and their transcriptional partners are emerging as core regulators of mitochondrial biogenesis and the oxidative fiber program, our understanding of the regulatory cascade that controls the development and function of fast-twitch glycolytic muscle is remarkably limited. The overall goal of this proposal is to explore novel mechanisms that regulate glycolytic muscle formation and investigate their role in the pathogenesis of insulin resistance during chronic caloric excess. In preliminary studies, we have identified BAF60c, a subunit of the SWI/SNF chromatin- remodeling complexes that interacts with other transcription factors, as a novel regulator of fast glycolytic muscle formation. Further we have delineated key molecular components of this regulatory cascade. In this proposal, we will first use gain- and loss- of-function mouse models to establish the physiological role of this pathway in the regulation of metabolic and contractile specification of fast glycolytic muscle. We will dissect the core molecular components involved, and assess the role of glycolytic muscle in the development of diet-induced insulin resistance. Successful completion of this project will provide novel insights into the mechanistic basis of glycolytic muscle development and plasticity, and shift the current paradigm on interrelationship between muscle fiber types and the pathogenesis of insulin resistance. PUBLIC HEALTH RELEVANCE: Metabolic syndrome is linked to increased risk for type 2 diabetes, cardiovascular disease, and non-alcoholic steatohepatitis, and has become a serious public health challenge for the US and the rest of the world. While it has been recognized that insulin resistance is an early pathogenic event in disease progression, the mechanisms that regulate tissue and systemic insulin sensitivity remain poorly understood. We propose to use state-of-the-art molecular, genetic, and metabolic tools to establish the significance of this new pathway in muscle function, dissect novel regulatory components, and assess the cause and effect relationship between muscle metabolism and insulin resistance.